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LETTER TO THE EDITOR

Pro-Drugs in In Vitro Experiments

Department of Pharmacology and Clinical Pharmacology; Ankara University School of Medicine; Ankara, Turkey; hergun{at}medicine.ankara.edu.tr

To the Editor:

Herbert et al. presented that acetaminophen impaired intestinal peristalsis whereas dipyrone did not. This is an interesting result; however, it raises several questions about the pharmacological effect of dipyrone (1).

Dipyrone clearly has a smooth muscle relaxant effect, as presented in several in vitro and clinical studies (2–6). According to the results of these studies, the combined pharmaceutical preparation of dipyrone with spasmolytic drugs are no longer available and single pharmaceutical forms are more commonly used in clinical practice (2). In contrast, Herbert et al. reported that acetaminophen, not dipyrone, is able to block the peristaltic activity of guinea pig small intestine (1). The authors state that their results are in accordance with the previous studies of Hernandez-Delgadillo et al. and Rupp et al. (7,8). However, in the literature there are other studies showing that dipyrone has an inhibitory effect on the acetylcholine-induced or electrically stimulated guinea pig ileum contraction (5,6). Controversial results in different studies are not rare in the literature and may have several explanations. One of the reasons may be the preparation of the substances for the in vitro use, which I want to emphasize.

In my opinion, the method the authors used to test whether dipyrone has any effects on small intestine peristaltic activity may have several limitations.

First, although dipyrone is not always considered a pro-drug in in vitro studies, the active metabolites, except the main metabolite 4-methylaminoantipyrine (4-MAA), are enzymatically converted from 4-MAA (9). It is not clear which of the metabolites of dipyrone are involved in the effects of dipyrone (i.e., analgesic, antipyretic, anticonvulsant, or antispasmodic effects) (10). There is only one study that correlates the serum dipyrone level and the analgesic efficacy of dipyrone. It reports that the saliva concentrations of dipyrone metabolites 4-MAA and 4-aminoantipyrine (4-AA) are correlated with the analgesic activity of dipyrone (11). Moreover, dipyrone is not apparent in plasma when administered orally, which is the most common route of administration, and dipyrone is only briefly detectable in the serum for approximately 15 min after IV administration (9).

Even with an assumption that 4-MAA is the only metabolite responsible for the effects produced by dipyrone, there is another point: that the hydrolysis of dipyrone to 4-MAA is time-dependent, as are all chemical reactions. This may have consequences when dipyrone is added into in vitro organ bath systems and the effect is observed only for a short time.

A recent article presents a systematic evaluation of the hydrolysis kinetic of dipyrone to 4-MAA (12). In this article it is clearly demonstrated that the dipyrone concentration, temperature, and pH of the solutions are all main factors affecting the hydrolysis kinetic of dipyrone. A simple extrapolation of this data to the results of Herbert et al. indicates that an observation period of 1 h would not be sufficient for a complete hydrolysis of dipyrone to the main metabolite 4-MAA. As a result, it would not be possible to know whether dipyrone really has no effect on the peristalsis of small intestine.

In conclusion, although dipyrone has been in clinical practice since 1922, which is a long time to explore the pharmacokinetic and pharmacodynamics properties, this does not fully apply for dipyrone. I want to emphasize once more that, especially for dipyrone but actually for all pro-drugs, it is not a good decision to use a pro-drug in in vitro and even in vivo systems without considering that the pharmacological active compound is the metabolite rather than the pro-drug itself.

References

1. Herbert MK, Weis R, Holzer P, Roewer N. Peristalsis in the guinea pig small intestine in vitro is impaired by acetaminophen but not aspirin and dipyrone. Anesth Analg 2005;100:120–7.[Abstract/Free Full Text]
2. Fendrich Z. Metamizol: A new effective analgesic with a long history. Overview of its pharmacology and clinical use. Cas Lek Cesk 2000;139:440–4.[Medline]
3. Ergun H, Ayhan IH, Tulunay FC. Pharmacological characterization of metamizol-induced relaxation in phenylephrine-precontracted rabbit thoracic aorta smooth muscle. Gen Pharmacol 1999;33:237–41.[Medline]
4. Brandstatter G, Schinzel S, Wurzer H. Influence of spasmolytic analgesics on motility of sphincter of Oddi. Dig Dis Sci 1996;41:1814–8.[Medline]
5. Schroth HJ, Garth H, Rupp S, Steinstrasser A. Effects of metamizole on the motility of the urinary tract: A quantitative analysis of the excretory phase of serial renal scintigraphy. Fortschr Med 1986;104:378–82.[Medline]
6. Ivanov D, Staneva-Stoycheva D. On some presynaptic effects of meramyzole (analgine-pharmachim). Acta Physiol Pharmacol Bulg 1984;10:34–41.[Medline]
7. Hernandez-Delgadillo GP, Ventura MR, Diaz Reval MI, et al. Metamizol potentiates morphine antinociception but not constipation after chronic treatment. Eur J Pharmacol 2002;441:177–83.[Web of Science][Medline]
8. Rupp S, Schroth HJ, Hildebrandt U, et al. The effect of metamizole on gastric emptying and small intestine transit in the rat. Arzneimittelforschung 1987;37:1051–3.[Medline]
9. Levy M, Zylber-Katz E, Rosenkranz B. Clinical pharmacokinetics of dipyrone and its metabolites. Clin Pharmacokinet 1995;28:216–34.[Web of Science][Medline]
10. Ergun H, Uzbay IT, Celik T, et al. Dipyrone inhibits ethanol withdrawal and pentylenetetrazol-induced seizures in rats. Drug Dev Res 2001;53:254–9.
11. Rohdewald P, Drehsen G, Milsmann E, Derendorf H. Relationship between saliva levels of metamizol metabolites, bioavailability and analgesic efficacy. Arzneimittelforschung 1983;33:985–8.[Medline]
12. Ergun H, Frattarelli DA, Aranda JV. Characterization of the role of physicochemical factors on the hydrolysis of dipyrone. Pharm Biomed Anal. 2004;35:479–87.

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